The endogenous opioid-like peptide, nociceptin (also referred to as orphanin FQ), was first described in the central nervous system, and most research in this field has focused on the CNS effects. Nociceptin binds to a specific receptor named opioid receptor-like one (ORL1) with much greater affinity than to the three classical subtypes of opioid receptors. Effects of nociceptin in the CNS include: hyperalgesia/hypoalgesia, stimulation of appetite and gnawing, increased (low doses) or decreased (high doses) locomotion, impaired learning, and dysphoria. However, nociceptin also exerts important effects outside the CNS. Thus, low doses of nociceptin increase the renal excretion of water and decrease urinary sodium excretion (i.e., produces a selective water diuresis) which render this compound interesting for the treatment of hyponatremia (Daniel R. Kapusta, Life Science, 60:15-21, 1997) (U.S. Pat. No. 5,840,696). When administered centrally (i.c.v.) or at high doses peripherally (i.v. bolus or infusion), nociceptin decreases blood pressure, heart rate and peripheral sympathetic nerve activity.
Dooley et al. (The Journal of Pharmacology and Experimental Therapeutics, 283(2):735-741, 1997) have shown that a positively charged hexapeptide having the amino acid sequence Ac-RYY(RK)(WI)(RK)-NH2, where the brackets show allowable variation of amino acid residue, acts as a partial agonist of the nociceptin receptor ORL1. Said hexapeptide was identified from a combinatorial peptide library and the sequence is unique without homology or similarity to the nociceptin heptadecapeptide. However, said hexapeptide is too unstable to yield a satisfactory medicament.
WO 99/44627 discloses the use of hexapeptides including the hexapeptides discovered by Dooley et al. for the manufacture of a pharmaceutical composition for the treatment of the following conditions: Migraine, type II diabetes, septic shock, inflammation and vasomotor disturbances. It is shown that the hexapeptide Ac-Arg-Tyr-Tyr-Arg-Trp-Lys-NH2 inhibits depressor response to spinal cord stimulation.
Considering that ORL1 agonists including the hexapeptide discovered by Dooley et al. as well as true nociceptin analogues are expected to have serious CNS side effects, if exposed to the brain, which are observed at dose levels higher than those required to elicit water diuresis in rats, it is a major objective of the present invention to provide novel conjugated peptides having the nociceptin-like activity of said hexapeptide or binding activity at the ORL1 receptor, but acting selectively outside the CNS. It is a further object of the invention to provide novel conjugated peptides having the nociceptin-like activity of said hexapeptide or binding activity at the ORL1 receptor and having improved stability. Moreover, it is an object of the invention to provide novel conjugated peptides having nociceptin-like activity or binding activity at the ORL1 receptor and/or at a yet unidentified receptor in kidney tissue.
This objective is achieved with the peptide conjugates of the present invention comprising hexapeptides modified C- and/or N-terminally by conjugation to short charged peptide chains.